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PDBsum entry 1knu

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protein ligands Protein-protein interface(s) links
DNA binding protein PDB id
1knu
Jmol
Contents
Protein chain
265 a.a. *
Ligands
YPA
Waters ×32
* Residue conservation analysis
PDB id:
1knu
Name: DNA binding protein
Title: Ligand binding domain of the human peroxisome proliferator activated receptor gamma in complex with a synthetic agonist
Structure: Peroxisome proliferator activated receptor gamma. Chain: a, b. Fragment: ligand binding domain. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Tissue: adipose tissue. Gene: pparg, nr1c3. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Biol. unit: Dimer (from PQS)
Resolution:
2.50Å     R-factor:   0.224     R-free:   0.264
Authors: L.A.Svensson,S.B.Mortensen,J.Fleckner,H.F.Woeldike
Key ref: P.Sauerberg et al. (2002). Novel tricyclic-alpha-alkyloxyphenylpropionic acids: dual PPARalpha/gamma agonists with hypolipidemic and antidiabetic activity. J Med Chem, 45, 789-804. PubMed id: 11831892 DOI: 10.1021/jm010964g
Date:
19-Dec-01     Release date:   19-Dec-02    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P37231  (PPARG_HUMAN) -  Peroxisome proliferator-activated receptor gamma
Seq:
Struc:
505 a.a.
265 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     nucleus   1 term 
  Biological process     steroid hormone mediated signaling pathway   2 terms 
  Biochemical function     DNA binding     4 terms  

 

 
DOI no: 10.1021/jm010964g J Med Chem 45:789-804 (2002)
PubMed id: 11831892  
 
 
Novel tricyclic-alpha-alkyloxyphenylpropionic acids: dual PPARalpha/gamma agonists with hypolipidemic and antidiabetic activity.
P.Sauerberg, I.Pettersson, L.Jeppesen, P.S.Bury, J.P.Mogensen, K.Wassermann, C.L.Brand, J.Sturis, H.F.Wöldike, J.Fleckner, A.S.Andersen, S.B.Mortensen, L.A.Svensson, H.B.Rasmussen, S.V.Lehmann, Z.Polivka, K.Sindelar, V.Panajotova, L.Ynddal, E.M.Wulff.
 
  ABSTRACT  
 
Synthesis and structure-activity relationships of tricyclic alpha-ethoxy-phenylpropionic acid derivatives guided by in vitro PPARalpha and PPARgamma transactivation data and computer modeling led to the identification of the novel carbazole analogue, 3q, with dual PPARalpha (EC(50) = 0.36 microM) and PPARgamma (EC(50) = 0.17 microM) activity in vitro. Ten days treatment of db/db mice with 3q improved the insulin sensitivity, as measured by OGTT, better than that seen with both pioglitazone and rosiglitazone treatment, suggesting in vivo PPARgamma activity. Likewise, 3q lowered plasma triglycerides and cholesterol in high cholesterol fed rats after 4 days treatment, indicating in vivo PPARalpha activity. Investigations of the pharmacokinetics of selected compounds suggested that extended drug exposure improved the in vivo activity of in vitro active compounds.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20496064 J.Fidelak, S.Ferrer, M.Oberlin, D.Moras, A.Dejaegere, and R.H.Stote (2010).
Dynamic correlation networks in human peroxisome proliferator-activated receptor-γ nuclear receptor protein.
  Eur Biophys J, 39, 1503-1512.  
20338488 P.Natarajan, K.K.Ray, and C.P.Cannon (2010).
High-density lipoprotein and coronary heart disease: current and future therapies.
  J Am Coll Cardiol, 55, 1283-1299.  
19746174 S.N.Lewis, J.Bassaganya-Riera, and D.R.Bevan (2010).
Virtual Screening as a Technique for PPAR Modulator Discovery.
  PPAR Res, 2010, 861238.  
19067454 Y.Tanrikulu, O.Rau, O.Schwarz, E.Proschak, K.Siems, L.Müller-Kuhrt, M.Schubert-Zsilavecz, and G.Schneider (2009).
Structure-based pharmacophore screening for natural-product-derived PPARgamma agonists.
  Chembiochem, 10, 75-78.  
18665581 A.S.Felts, B.S.Siegel, S.M.Young, C.W.Moth, T.P.Lybrand, A.J.Dannenberg, L.J.Marnett, and K.Subbaramaiah (2008).
Sulindac derivatives that activate the peroxisome proliferator-activated receptor gamma but lack cyclooxygenase inhibition.
  J Med Chem, 51, 4911-4919.  
18083521 D.Chaturvedi, S.Ray, A.K.Srivastava, and R.Chander (2008).
Omega-(2-Naphthyloxy) amino alkanes as a novel class of anti-hyperglycemic and lipid lowering agents.
  Bioorg Med Chem, 16, 2489-2498.  
17462987 A.L.Ambrosio, S.M.Dias, I.Polikarpov, R.B.Zurier, S.H.Burstein, and R.C.Garratt (2007).
Ajulemic acid, a synthetic nonpsychoactive cannabinoid acid, bound to the ligand binding domain of the human peroxisome proliferator-activated receptor gamma.
  J Biol Chem, 282, 18625-18633.
PDB code: 2om9
17357171 G.Fracchiolla, A.Laghezza, L.Piemontese, G.Carbonara, A.Lavecchia, P.Tortorella, M.Crestani, E.Novellino, and F.Loiodice (2007).
Synthesis, Biological Evaluation, and Molecular Modeling Investigation of Chiral Phenoxyacetic Acid Analogues with PPARalpha and PPARgamma Agonist Activity.
  ChemMedChem, 2, 641-654.  
17403688 G.Pochetti, C.Godio, N.Mitro, D.Caruso, A.Galmozzi, S.Scurati, F.Loiodice, G.Fracchiolla, P.Tortorella, A.Laghezza, A.Lavecchia, E.Novellino, F.Mazza, and M.Crestani (2007).
Insights into the mechanism of partial agonism: crystal structures of the peroxisome proliferator-activated receptor gamma ligand-binding domain in the complex with two enantiomeric ligands.
  J Biol Chem, 282, 17314-17324.
PDB codes: 2i4j 2i4p 2i4z
17441160 H.Kakei, R.Tsuji, T.Ohshima, H.Morimoto, S.Matsunaga, and M.Shibasaki (2007).
Catalytic asymmetric epoxidation of alpha,beta-unsaturated esters with chiral yttrium-biaryldiol complexes.
  Chem Asian J, 2, 257-264.  
17937915 J.B.Bruning, M.J.Chalmers, S.Prasad, S.A.Busby, T.M.Kamenecka, Y.He, K.W.Nettles, and P.R.Griffin (2007).
Partial agonists activate PPARgamma using a helix 12 independent mechanism.
  Structure, 15, 1258-1271.
PDB codes: 2q59 2q5p 2q5s 2q61 2q6r 2q6s
17960326 P.Markt, D.Schuster, J.Kirchmair, C.Laggner, and T.Langer (2007).
Pharmacophore modeling and parallel screening for PPAR ligands.
  J Comput Aided Mol Des, 21, 575-590.  
17048123 Q.L.Zeng, H.Q.Wang, Z.R.Liu, B.G.Li, and Y.F.Zhao (2007).
Facile synthesis of optically pure (S)-3-p-hydroxyphenyllactic acid derivatives.
  Amino Acids, 33, 537-541.  
16402897 A.C.Li, and W.Palinski (2006).
Peroxisome proliferator-activated receptors: how their effects on macrophages can lead to the development of a new drug therapy against atherosclerosis.
  Annu Rev Pharmacol Toxicol, 46, 1.  
16634983 H.E.Lebovitz (2006).
Insulin resistance--a common link between type 2 diabetes and cardiovascular disease.
  Diabetes Obes Metab, 8, 237-249.  
16804025 J.O.Nehlin, J.P.Mogensen, I.Petterson, L.Jeppesen, J.Fleckner, E.M.Wulff, and P.Sauerberg (2006).
Selective PPAR agonists for the treatment of type 2 diabetes.
  Ann N Y Acad Sci, 1067, 448-453.  
16892334 N.Dell'Uomo, E.Tassoni, T.Brunetti, P.Pessotto, A.F.Sciarroni, F.M.Milazzo, F.De Angelis, A.Peschechera, M.O.Tinti, P.Carminati, and F.Giannessi (2006).
2-{3-[2-(4-chlorophenyl)ethoxy]phenylthio}-2-methylpropanoic acid: a fibrate-like compound with hypolipidemic and antidiabetic activity.
  ChemMedChem, 1, 49-53.  
16200561 J.Malmstrøm, L.Hansen, A.Ryager, and H.Olsen (2005).
High speed development work by preparation of an "in-hand" library of NMR-quantified degradation products.
  J Pharm Sci, 94, 2549-2567.  
15655531 L.C.Pickavance, C.L.Brand, K.Wassermann, and J.P.Wilding (2005).
The dual PPARalpha/gamma agonist, ragaglitazar, improves insulin sensitivity and metabolic profile equally with pioglitazone in diabetic and dietary obese ZDF rats.
  Br J Pharmacol, 144, 308-316.  
15271292 A.L.Parrill, V.M.Sardar, and H.Yuan (2004).
Sphingosine 1-phosphate and lysophosphatidic acid receptors: agonist and antagonist binding and progress toward development of receptor-specific ligands.
  Semin Cell Dev Biol, 15, 467-476.  
14597889 J.Beckman, A.Raji, and J.Plutzky (2003).
Peroxisome proliferator activated receptor gamma and its activation in the treatment of insulin resistance and atherosclerosis: issues and opportunities.
  Curr Opin Cardiol, 18, 479-485.  
12665417 M.Patel, and P.J.Rybczynski (2003).
Treatment of non-insulin-dependent diabetes mellitus.
  Expert Opin Investig Drugs, 12, 623-633.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.